title: Targeting the histidine pathway in Mycobacterium tuberculosis.
abstract: Worldwide, tuberculosis is the leading cause of morbidity and mortality due to a single bacterial pathogen, Mycobacterium tuberculosis (Mtb). The increasing prevalence of this disease, the emergence of multi-, extensively, and totally drug-resistant strains, complicated by co-infection with the human immunodeficiency virus, and the length of tuberculosis chemotherapy have led to an urgent and continued need for the development of new and more effective antitubercular drugs. Within this context, the L-histidine biosynthetic pathway, which converts 5-phosphoribosyl 1-pyrophosphate to L-histidine in ten enzymatic steps, has been reported as a promising target of antimicrobial agents. This pathway is found in bacteria, archaebacteria, lower eukaryotes, and plants but is absent in mammals, making these enzymes highly attractive targets for the drug design of new antimycobacterial compounds with selective toxicity. Moreover, the biosynthesis of L-histidine has been described as essential for Mtb growth in vitro. Accordingly, a comprehensive overview of Mycobacterium tuberculosis histidine pathway enzymes as attractive targets for the development of new antimycobacterial agents is provided, mainly summarizing the previously reported inhibition data for Mtb or orthologous proteins.
authors.affiliation: Instituto Nacional de Ciência e Tecnologia em Tuberculose (INCT-TB), Centro de Pesquisas em Biologia Molecular e Funcional (CPBMF), Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), 90619-900, Porto Alegre, RS, Brazil. pablo.machado@pucrs.br.
authors.forename: Juleane
authors.initials: J
authors.lastname: Lunardi
authors.forename: José Eduardo S
authors.initials: JE
authors.lastname: Nunes
authors.forename: Cristiano V
authors.initials: CV
authors.lastname: Bizarro
authors.forename: Luiz Augusto
authors.initials: LA
authors.lastname: Basso
authors.forename: Diógenes Santiago
authors.initials: DS
authors.lastname: Santos
authors.forename: Pablo
authors.initials: P
authors.lastname: Machado
mesh_terms: D001276:ATP Phosphoribosyltransferase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019747:Aldose-Ketose Isomerases / Q000235:genetics / Q000378:metabolism; D000619:Aminohydrolases / Q000235:genetics / Q000378:metabolism; D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004798:Enzymes / Q000235:genetics / Q000378:metabolism*; D006639:Histidine / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*
chemical_list: D000995:Antitubercular Agents; D004798:Enzymes; D006639:Histidine; D001276:ATP Phosphoribosyltransferase; C087227:imidazole glycerol phosphate synthase; D000619:Aminohydrolases; D019747:Aldose-Ketose Isomerases